Structure, function and regulation of carboxylesterases

Chemico-Biological Interactions 162 (2006) 195–211

Mini review

Structure, function and regulation of carboxylesterases Tetsuo Satoh a,b,∗ , Masakiyo Hosokawa a,c b

a Graduate School of Pharmaceutical Sciences, Chiba University, Japan HAB Research Laboratories, Cornea Center Building, 3rd Floor, Ichikawa General Hospital, Sugano, Ichikawa, Chiba 272-8513, Japan c Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Japan

Received 27 March 2006; received in revised form 14 June 2006; accepted 1 July 2006 Available online 6 July 2006

Abstract This review covers current developments in molecular-based studies of the structure and function of carboxylesterases. To allay the confusion of the classic classification of carboxylesterase isozymes, we have proposed a novel nomenclature and classification of mammalian carboxylesterases on the basis of molecular properties. In addition, mechanisms of regulation of gene expression of carboxylesterases by xenobiotics and involvement of carboxylesterase in drug metabolism and enzyme induction are also described. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Carboxylesterases; Function; Drug metabolism; Gene expression; Molecular structure; Regulation; Enzyme induction; Novel nomenclature and classification

Contents 1. 2. 3.

4. 5.

6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Novel classification and nomenclature of mammalian CarbEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure–activity relationship of mammalian CarbEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Localization and expression of CarbEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Structure and catalytic mechanism of CarbE isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene structure and regulation of CarbE isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Possible role of CarbEs in drug metabolism and pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Drug metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enzyme induction of CarbE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A novel biomarker of organophosphate insecticide exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

196 198 198 198 199 202 203 203 205 206 207 207 208 208

Abbreviations: CarbEs, CES, carboxylesterases; AChE, acetylcholinesterase; CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidinol]carbonyloxycamptothecine; UGT, UDP-glucuronosyltransferase; ER, endoplasmic reticulum; SNP, single nucleotide polymorphism; TCDD, tetrachlorodibenzop-dioxin ∗ Corresponding author. Tel.: +81 47 329 3563; fax: +81 47 329 3565. E-mail addresses: [email protected], [email protected] (T. Satoh). 0009-2797/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2006.07.001

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1. Introduction The present review highlights the importance of structure in delineating overall function, substrate specificity, regulation and localization of mammalian carboxylesterases (CarbEs). They are ␣,␤-hydrolasefold protein and comprise a multigene superfamily [1]. Structural considerations emerge from the genes

encoding the family. Diversity in the structure and ultimately function and cellular localization of the gene product is achieved through gene doubling, alternative mRNA processing and post-translational modification. The expression of CarbEs is ubiquitous with high levels in various tissues. Some of the isozymes are destined for export into the plasma. Others are associated with cell membrane such as endoplasmic reticulum

Table 1 Classification and nomenclature for mammalian carboxylesterase Gene symbol

Trivial name

Species

Homology

Genebank

CES1A1 CES1A2 CES1A3 CES1A4 CES1A5 CES1B1 Ces1B2 Ces1B3 CES1B4 CES1B5 CES1C1 CES1C2 CES1C3 CES1C4 CES1C5 Ces1D1 CES1D2 Ces1E1 CES1F1 CES1G1 Ces1G2 Ces1H1 CES1H2 CES1H3 CES1H4 CES2A1 CES2A2 CES2A3 Ces2A4 CES2A5 Ces2A6 Ces2A7 CES2A8 CES2A9 CES2A10 CES2A11 CES2A12 CES3A1 CES3A2 CES4A1 CES4A2 CES4B1 Ces4B2 CES4C1 CES5A1 CES5B1 CES5B2

Macropharge/hCE1/HU1a/ CES HU1b Human placenta Monkey CES1 rabbit 1 Hamster AT31 Mouse TGH Mouse CES MH1 Rat ES-10 Rat BC078681 Dog CESD1 Felica-CESK1 Felis-CES1 Pig CES1 Pig CES Mouse ES22 (Egasin) Rat ES-3 (Egasin) Mouse EST1 Bovine-REH Rat CES 60KDa Mouse EST-N Mouse ES-4 Rat hydrolaseC Rat ES-4/hydrolaseB Rat CES RL1 Human CES2/hCE2 Rabbit 2 HamsterAT41 Mouse BC022148 Bovine CES2 Mouse mCES2 Mouse CESBC015286 Rat BC097486 Rat SICES Rat CES RL4 (mCES2) Hamstar AT51 Rat CES6 Human hCE3 Mouse ES31 Dog CAUXIN Felica CAUXIN Rat CUXIN Mouse CAUXIN Human AcylCoA Human AADAC Mouse AADAC Rat AADAC

Homo sapiens H. sapiens H. sapiens Macaca fascicularis Orytolagus cuniculus Mesocricetus auratus Mus musculus M. musculus Rattus norvegicus R. norvegicus Canis familiaris Felis catus F. catus Sus scrofa S. scrofa M. musculus R. norvegicus M. musculus Bos taurus R. norvegicus M. musculus M. musculus R. norvegicus R. norvegicus R. norvegicus H. sapiens O. cuniculus M. auratus M. musculus B. taurus M. musculus M. musculus R. norvegicus R. norvegicus R. norvegicus M. auratus R. norvegicus H. sapiens M. musculus C. familiaris F. catus R. norvegicus M. musculus H. sapiens H. sapiens M. musculus R. norvegicus

100.0 99.3 93.3 92.9 81.1 79.0 78.0 77.9 77.6 76.9 79.7 78.5 78.0 77.6 76.6 75.5 75.0 73.2 71.5 69.1 65.5 67.3 67.4 67.0 66.0 46.8 46.9 46.2 45.9 43.8 43.5 43.5 44.3 44.1 42.8 45.7 44.5 44.8 41.1 45.5 45.5 42.4 41.9 36.8 31.3 29.9 25.6

L07765/AB119995 AB119996 MN016280 AB010633 AF036930 D50578 AF378751 AB023631 X51974 BC078681 AB023629 AB114676 AB094147 AF064741 X63323 S8091 X81395 Y12887 AY369075 M20629 M57960 BC013479 U10698 X81825 AB023630 U60553 P14943 (protein) D50577 BC022148 NM001034260 BC031170/BC015290 BC015286 BC097486 AB010632 AB010635/AB191005 D28566 NM144743 XM016735 S64130 AB186392 AB045377 AF479659 AB186393 AK056109 NM001086 BC054823 BC088143

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(ER) with its catalytic function directed extracellularly [2–12]. Expression profiles of gene encoding CarbEs are highly regulated during development by nutritional sta-

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tus, hormonal factors and xenobiotics. Although the consequences of regulation of CarbEs by drugs and chemicals have been intensively studied [11,13,16,17], relatively little is known about the mechanisms by which

Fig. 1. Phylogenetic tree of the carboxylesterase superfamily, using a simple unweight pair-group method of analysis (UPGMA) dendrogram.

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esterases are regulated by physiological factors. Recent developments have included more detailed biochemical characterization of mammalian CarbE enzymes and genes, leading to a better understanding of the biochemical significance and physiological role of CarbEs. This review addresses the significant differences of molecular structure and function of recently identified CarbEs, and proposes a novel nomenclature for mammalian CarbE isozymes that is based on the nucleotide sequences of the genes encoding the individual CarbE isozymes. 2. Novel classification and nomenclature of mammalian CarbEs According to the classification of esterases by Aldridge [18], the serine super family of esterases, i.e., acetylcholinesterase(AChE), butyrylcholinesterase and CarbE, fall into the B-esterase group. CarbE iszymes were initially classified by their substrate specificity and pI. However, this classification is ambiguous in overlapping substrate specificities. A single esterolytic reaction is frequently mediated by several kinds of enzymes. Recent studies on esterases, as with other enzymes concerned with xenobiotic metabolism, have afforded evidence of multiple forms. It seems almost impossible to classify these CarbE isozymes based on their substrate specificity along the lines of the I.U.B. Classification, because the individual hydrolases exhibit properties of CarbE, lipase or both. Mentlein et al. [19] proposed to classify these hydrolases as “unidentified CarbE (EC 3.1.99.1 to 3.1.99.x).” Recently, Satoh and Hosokawa [11] proposed a novel classification and nomenclature of mammalian carboxylesterase isozymes. Table 1 summarizes the sequence identities of CES isozymes based on human liver CarbE [11]. We have thought CES comprises a superfamily that is based on high homology and similarity of characteristics. Therefore, we tried to classify CES isozymes into five subfamilies, CES 1, CES 2, CES 3, CES4 and CES 5 (Fig. 1). The CES 1 family includes the major forms of CES isozymes (more than 60% homology of human CES). Thus, they could be divided into eight subfamilies through CES 1A to CES 1H. The CES 1A subfamily includes the major forms of human CESs, and the major isoforms of rat, dog, rabbit and mouse CES. The CES 1H subfamily includes RL1, ML1 and Hydrolase B and C that catalyze long-chain acyl-CoA hydrolysis. The members of the CES 1G family are all a secretary type of CESs. In contrast, the CES 2 family includes human intestinal CES (hCE2,), rat RL4 (rCES2), rat intestinal CES, mouse ML3 (mCES2,), rabbit form 2 and hamster AT51, which mainly expressed

in small intestines. CES 3 includes ES-male and human hCE3. The CES 4 families were currently identified as CES families by Miyazaki et al. [20]. They investigated the possible cause of proteinuria in healthy cats and discovered a 70 kDa glycoprotein, which was excreted as a major urinary protein in cat urine. They cloned the cDNA for this protein and characterized, the protein as having a CES-specific sequence, and then named the protein CAUXIN (carboxylesterase-like urinary excreted protein). The CES 5 family includes the 46.5 kDa CES isozymes, which have a structure different from other CES families. ES 46.5 kDa from mouse liver [21] and amido hydrolase of monkey liver [22] probably belong to this family. These groupings are similar to the results of the phylogenetic analysis (Fig. 1). 3. Structure–activity relationship of mammalian CarbEs The CarbEs comprise a multigene superfamily, the gene products of which are localized in the endoplasmic reticulum (ER) of many tissues [2–11,23,24]. These enzymes efficiently catalyze the hydrolysis of a variety of drugs or prodrugs containing ester- and amide-bonds to the respective free acids and alcohol. Since ester derivatives of therapeutic agents have been used as prodrugs, CarbEs are major determinants of the pharmacokinetic behavior of most prodrugs, and the activity can be influenced by direct interactions with a variety of compounds, either directly or by enzyme regulation [13–15]. 3.1. Localization and expression of CarbEs Fig. 2 shows the localization of the mammalian CarbEs localized in the liver endoplasmic reticulum. The expression of CarbEs is observed in the liver, small intestine, kidney, and lung. Among various tissues of animals, the highest hydrolase activity is typically found in the liver [6] and other tissues, such as testis, kidney, and plasma [12]. Recently, Li et al. [25] reported that unlike mouse, rat, rabbit, horse and cat, human plasma contains no carboxylesterases, and butyrylcholinesterase and paraoxonase are responsible for the hydrolysis of compounds having ester and amide bonds. Similarly, we have found that the human plasma hydrolase activity was not inhibited by bis-p-nitrophenylphosphate (BNPP) which was a specific inhibitor of CarbEs, indicating that no CarbEs were contained in human plasma (Hosokawa et al., unpublished data). Since a significant number of drugs are metabolized by CarbEs, altering the activities of these enzymes expressed in each tissue has important clinical implications. However, little is known about

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Fig. 2. Proposed mechanism for the action of carboxylesterase. The catalytic triad (Ser, Glu, His) in the tetrahedral addition intermediate is stabilized by the low barrier hydrogen bonds.

the differences in structure and hydrolytic capabilities of human CarbE isozymes. Structural characterizations of CarbE isozymes, their expression in various tissues, and their substrate specificities provide important insights into the molecular basis for their functional differences in humans. Fox et al. [26] reported the altered expression of TEF-1 and CES-2 in Barrett’s esophagus and associated adenocarcinoma. Yamada et al. [9] reported the circulation to brain interstitial fluid. Thus, the presence of CarbEs in capillary endothelial cells is consistent with the enzyme’s acting to protect the central nervous system from toxic esters and may be a component of the so-called blood–brain barrier system. Recombinant DNA and expression techniques have been introduced to the field of CarbE as a means of clarifying the substrate specificity of each isozyme, elucidate the catalytic mechanism of CarbEs, and delineate the role of CarbE in the ER. Proteins with this carboxyterminal bind the KDEL receptor and associate with the ER membrane. Sanghani et al. [27] showed that multiple genes are highly expressed in liver and small intestine, important tissues for retinoid metabolism. Later, Sanghani et al. [28] reported the cloning and expression of a new human isozyme, CES 3, that belongs to class 3. They found that CPT-11 and related compounds can be metabolized by carboxylesterases to SN-38. CES2 has the highest catalytic activity among these three carboxylesterases. Pfutzer et al. [29] reported that chronic ethanol consumption induced expression of fatty acid ethyl ester (FAEE)-related genes in the pancreas and liver. This upregulation may be a central mechanism leading to acinar cell injury.

3.2. Structure and catalytic mechanism of CarbE isozymes The present chapter deals primarily with the characteristics and the molecular cloning of individuals that were recently identified to be CarbE isozymes. As indicated in Fig. 2, several proteins of ER lumen have the common carboxyl-terminal sequence KDELCOOH, and the structural motif is essential for retention of the protein in the luminal site of ER through the KDEL receptor bound to the ER membrane [11,30,31]. Korza and Ozols [32] and Ozols [33] established the primary structures of two microsomal esterases purified from rabbit liver and designated them 60 kDa esterase forms 1 and 2. These two forms of CarbE have the consensus sequence for the endoplasmic reticulum retention tetra-peptide (HIEL-COOH or HTEL-COOH in the one-letter code amino acid) that is recognized with the luminal side of the KDEL receptor. Robbi’s group [34] reported cDNA cloning of rat liver pI 6.1 esterase (ES10) and pI 5.5 esterase (ES-3, egasyn). This was the first report to show that cDNA of liver CarbE has the consensus sequence of the ER retention tetrapeptide (HVELCOOH). Later, Robbi and Beaufay [35] isolated a cDNA clone of another rat liver pI 5.5 esterase (ES-3, egasyn) that has the consensus sequence of the ER retention tetrapeptide (HTEL-COOH). In a case of mouse liver microsomal CarbE, the carboxyl terminal amino acid sequence of clone Es-N is HTEHK-COOH, which differs from the consensus sequence of the ER retention signal. The other clone encoded egasyn, an accessory protein of

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Fig. 3. Diagrammatic comparison of deduced amino acid sequences of rat, mouse, hamster, and human carboxylesterase isozymes. Each trivial name is listed in the text.

␤-glucuronidase in the liver microsomes [36]. Egasyn is identical to CarbE, and it binds ␤-glucuronidase via its CarbE active site. Thus, it contains the consensus sequence of the ER retention signal (HTEL-COOH). Ovnic et al. [37] conducted genetic mapping and confirmed the location of an egasyn cDNA fragment in cluster 1 of the esterase region on chromosome 8. Shibata et al. [38] found that the human CarbE gene spanned approximately 30 kilobases (kb) and has 14 small exons. Many CarbEs have a signal peptide of 17–20 amino acid residues, including hydrophobic amino acid, for retention in the lumen of the ER (Fig. 3). In general, a bulky aromatic residue followed by a small neutral residue directly precedes the cleavage site [39]. Many CarbEs have four cysteines that may be involved in specific disulfide bonds. Among them Cys98 is the most highly conserved residue in many CES isozymes (Fig. 3). Cygler et al. [1] reported an important alignment of a collection of related amino acid sequences

of esterase, lipase and related proteins based on X-ray structures of Torpedo californica AChE and Geotrichum candidum lipase. According to these authors, Ser 203, Glu 336 and His 450 form a catalytic triad, and Gly 124Gly 125 may be part of an oxyanion hole. These residues are also highly conserved among CarbE isozymes. Thus, we have started mutation analysis [11]. Site-specific mutation of Ser 203 to The 203, Glu 336 to Ala 336 or His 450 to Ala 450, greatly reduced the CarbE activity towards substrates. Therefore, the mutagenesis confirmed the role for Glu 336 and His 450 in forming a putative charge relay system with active site Ser 203 [11]. In 1994, Frey et al. [40] investigated the formation of low barrier hydrogen bonds between His and Asp (Glu for CarbE) that facilitates the action of nucleophilic attack by the ␤-OH group of Ser on the acyl carbonyl peptide group in chymotrypsin. The catalytic triad in the tetrahedral addition intermediate is stabilized by the

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Fig. 4. A proposed mechanism for the formation of the tetrahedral intermadiate. (A) Hydrolysis of substrate start with an attack by the oxygen atom of the hydroxy group of Ser 203 on the carbonyl carbon atom of the substrate. (B) The carbon–oxygen bond of this carbonyl group becomes a single bond, and the oxygen atom acquires a net negative charge. The four atoms now bonded to the carbonyl carbon are arranged as in a tetrahedron. The formation of this transient tetrahedral intermediate from a substrate is made possible by hydrogen bonds between the negative charged oxygen anion (called an oxyanion) and main-chain NH group. This site is called oxyanion hole.

low barrier hydrogen bonds. According to their theory, we thought the low barrier hydrogen bond between Glu 336 and His 450 facilitates the action of nucleophilic attack by the ␤-OH group of Ser 203 on the carboxyl substrate group in CarbE (Fig. 4). In this mechanism, the His 450 removes a proton from the Ser 203 in the transition state for its addition to the acyl carbonyl substrate group. In the tetrahedral intermediate, Fig. 4 also shows the formation of low barrier hydrogen bonds between His 450 and Glu 336, and the transition state is stabilized by low barrier hydrogen bonds. These low barrier hydrogen bonds facilitate a mechanism that includes weak hydrogen bonds between the tetrahedral oxyanion and peptide N–H bonds contributed by Gly 123 and Gly 124, which stabilize the tetrahedral adduct on the substrate side of the transition state. Formation of the acyl–enzyme complex in the next step requires removal of a proton from His 450, so that the tetrahedral intermediate is disrupted in the acyl–enzyme intermediate. When the unbound portion of the alcohol group of the first substrate product substrate has diffused, a second step occurs in which the deacylation step is essentially the reverse of the acylation step, with a water molecule substituting for the alcohol group of the original sub-

strate. To clarify the catalytic mechanism of CarbE, mutation analysis of other structural domains, such as the site of salt bridges, the substrate binding site and glycosylation site, would be worthwhile. It is of interest that the sequences required for the hydrolytic capability at the catalytic triad (Glu, His, Ser) of CarbE, AChE, butyrylcholinesterase, and cholesterol esterase are highly conserved. This is a common structure of serine hydrolase superfamilies which are responsible for the hydrolysis of endogenous and exogenous compounds. Furthermore, these elements are strongly conserved among orthologous CarbEs from mouse, rat, rabbit, monkey and human. A three-dimensional model for human CarbE has been proposed based on the crystal structure coordinates of AChE and overlapping active sites with pancreatic lipase [41] and CarbE. The modeled structure shares the overall folding and topology of the proteins identified in the recently published crystal structures of the rabbit [41] and human CarbE [41,43]. As mentioned elsewhere in this review, CarbE has a three-dimensional ␣,␤-hydrolase fold that is a structural feature of all lipases [1] In general, the structure of CarbE may be viewed as comprising a central catalytic domain surrounded by ␣,␤ and regulatory domains

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[16,17,42–48]. In essence, the ␣,␤-hydrolase fold consists of a central ␤ sheet surrounded by a variable number of ␣ helices and accommodates a catalytic triad composed of Ser, His and a carboxylic acid. The residues that compose the catalytic domain of human CES1 are very highly conserved among orthologous CES1 proteins from different species (Fig. 4). This suggests that the catalytic function of these proteins is conserved across species. The catalytic triad is located at the bottom of a deep active site cleft approximately in the molecule and is comprised of a large flexible pocket on one side of Ser 203 and a small rigid pocket on the opposite side. The orientation and location of the active site provides an ideal hydrophobic environment for the hydrolysis of a wide variety of hydrophobic substrates. The small rigid active site pocket is adjacent to the oxyanion hole formed by Gly 123–124 and is lined by several hydrophobic residues [41]. Short acyl chains would be easily accommodated within the small rigid pocket. The larger flexible active site pocket is lined by several nonpolar residues and could accommodate larger or polycyclic molecules such as cholesterol. The large pocket is adjacent to a sidedoor secondary pore that would permit small molecules (substrates and reaction products) to enter and exit the active site [41]. Longer acyl chains may be oriented for catalysis in such a way that they extend through the side door. Indeed, the presence of a hydrophobic residue at position 423 in mouse and 425 in human is necessary for efficient hydrolysis of hydrophobic substrates, as mutation of Met present in position 423 of the related rat lung CarbE to Ile increased the CarbE activity towards a more hydrophobic substrate without affecting activity towards short-chain esters [53]. According to the X-ray crystal structure of the human CES1 this residue lines the flexible pocket adjacent to the side door [49]. Given the wide range of substrates that CarbEs are known to hydrolyze, the large flexible pocket confers the ability to hydrolyze many structurally distinct compounds, whereas the rigid pocket is much more selective with regard to the substrates that may be accommodated. 4. Gene structure and regulation of CarbE isozymes Both the murine [11] and human [4,38,46] CES1 genes span about 30 kb and contain 14 small exons. Recently, sequencing of the mouse and human genomes were completed, enabling detailed sequence comparisons. The previously published sequences of the individual exons, splice junctions, size of the introns and restriction sites within the murine and human CarbE genes

are consistent with their respective genes sequenced by the mouse and human genome projects. Therefore, the organization of the CarbE gene is evolutionarily conserved in mice and humans. Furihara et al. [49] reported that hepatocyte nuclear factor-4 alpha plays pivotal roles in the regulation of mouse CES2 gene transcription in mouse liver. Previous studies have mapped the human CarbE gene to chromosome 16 at 16q13–q22.1 [47,48]. This region is syntenic to a region of mouse chromosome 8 at 8C5 [47]. The murine CarbE Es22 [37] and Es1 [54] have been previously mapped to chromosome 8 (Fig. 5). The completion of the mouse genome sequencing project unambiguously demonstrated that the murine CarbE gene was located on the minus strand of chromosome 8 at 8C5 in a cluster of six CarbE genes that spans 260.6 kb in total. These six CarbE genes are presumed to have originated from repeated gene duplications of a common ancestral gene that encoded a CarbE [38] and subsequent evolutionary divergence occurred. Recent studies have shown that there are some differences between these families in terms of substrate specificity, tissue distribution, immunological properties and gene regulation. Therefore, the 5 -flanking regions of CES1 and CES2 genes were isolated from mouse, rat and human genomic DNAs by PCR amplification (Fig. 5). Two individual mouse CES genes (mCES MH1 and mCES ML1) [16] and two individual human CarbE genes (CES HU1a and HU1b) were found to belong to the CES1 family, and mouse mCES2 [57], rat rCES2 [16] and human CES HU3 genes were found to belong to the CES2 family. A TATA box does not precede the transcription start site of any of the CarbE promoters. CarbE promoters share several common binding sites for transcription factors among the same CarbE families, suggesting that orthologous CarbE genes have evolutionally conserved transcriptional regulatory patterns. Potential binding sites of CarbE promoters for transcriptional factors include Sp1, Sp3, C/EBP, USF1, NF-1, NFkB, PPARa, GR, SREBP, HNF1, HNF3 and HNF4 binding sites. In the case of human CES1 genes, we isolated two CarbE genes encoding human CES HU1, which were tentatively designated as CES HU1a and CES HU1b (Fig. 5). These genes are identical except for exon 1 and cis elements. Electrophoretic mobility shift assays and reporter gene assays demonstrated that SP1, C/EBP and NF-1 could bind to each responsive element of the CES HU1a promoter, but that C/EBP could not bind to responsive elements of the CES HU1b promoter. Wu et al. [50] reported the characterization of multiple promoters in the human carboxylesterase 2 gene.

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The structure of the CES2 gene promoter was different from that of the CES1 gene promoter (Fig. 5). More recently, we have shown tissue expression profiles of mCES2 and parts of the mechanism by which transcription of the mCES2 gene is regulated [51]. mCES2 is expressed in the liver, kidney, small intestine, brain, thymus, lung, adipose tissue and testis. We have also shown that Sp1, Sp3, and USF1 contribute to synergistic transactivation of the mCES2 promoter. Although involvement of other transcription factors in the regulation of the mCES2 gene expression cannot be assumed and further studies are needed to fully elucidate the mechanisms, our data indicate that Sp1, Sp3 and USF1 are indispensable factors for transcription of the mCES2 gene. The results of our present study have provided some clues for understanding the molecular mechanisms regulating mCES2 gene expression and would be an important step toward elucidation of physiological functions of mCES2 [51]. Recently, Wu et al. [52] identified 15 SNPs of CES 2 towards the rate of hydrolysis of irinotecan (CPT11) and procain in 78 normal individuals. One is in an exon, nine are in introns, three are in the 3 -untranslated region (UTR) and two are in the 5 -flanking region. Eight of SNPs loci have rare allele frequencies greater than 5%, of which three were greater than 20%. Kim et al. [53] reported 12 novel SNPs in the CES2 gene encoding human carboxylesterase 2 (hCE-2) from 153 Japanese individuals, who were administered irinotecan or steroidal drugs.

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5. Possible role of CarbEs in drug metabolism and pharmacokinetics 5.1. Drug metabolism Drug-metabolizing enzymes that are present predominantly in the liver are involved in biotransformation of both endogenous and exogenous compounds to polar products to facilitate their elimination. These reactions are categorized into phases I and II reactions. CarbEs show ubiquitous tissue expression profiles with the highest levels of CarbE activity present in liver microsomes in many mammals [4,5,11]. CarbEs are categorized as phase-I drug-metabolizing enzymes that can hydrolyze a variety of ester-containing drugs and prodrugs. Thus, CarbEs are one of most important enzymes involved in prodrug activation notably with respect to tissue distribution, up-regulation in tumor cells and turnover rates. Takai et al. [55] and others [17,24] compared hydrolysis of many drugs catalyzed by hCE-1 (pI 5.3) and hCE-2 (pI 4.5). Several angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, cilazapril, quinapril, temocapril, delapril and imidapril were studied. All of these drugs are ethyl esters with a large acyl group, and they are better substrates for hCE-1. Takai et al. [54] also reported that the local anesthetic drug procaine and the anticholinergic drug oxybutynin with large alcohol substitutes are substrates for hCE-2 but not hCE-1. Enzyme preference is less selective for

Fig. 5. Gene structure and 5 regulatory element of CES HU1a (CES1A1), CES HU1b (CES1A2) and CES HU3 (CES2A1) genes.

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substrates, such as camostat and dilazep, that have both large alcohol and acyl substituents [55]. The metabolism of anti-tumor drugs (CPT-11 and Capecitabin) [8,56,57] and narcotics (cocaine, heroin and meperidine) [16,48] by CarbEs were also studied. Otsuka et al. [58] investigated the expression of hCE in human lung cancer cells as well as the ability of these cells to convert CPT-11 to SN-38 using surgically resected tumor samples and cultured cell lines. They concluded that human lung cancer cells that expressed the enzyme converting CPT-11 to SN-38 may act as a chemotherapeutic agent together with SN-38 absorbed from the outside. Therefore, to assess the effects of CPT-11 prior to chemotherapy, it is important to check if lung cancer cells express hCE. Charasson et al. [59] studied the existence of functional polymorphisms in the gene encoding CarbE that could explain the individual variability in efficacy and toxicity of irinotecan, and concluded that the hCE2 gene presents several polymorphisms, none of which seems to be involved in irinotecan activation. In drug toxicity, mammalian CarbEs are involved in detoxification or metabolic activation of various drugs, environmental toxicants and carcinogens. Some CarbE isozymes are associated with hepatocarcinogenesis [7]. CarbEs also catalyze the hydrolysis of endogenous compounds such as short and long-chain acyl-glycerols, long-chain acyl-carnitine, and long-chain acyl-CoA esters. Satoh and Hosokawa [11] have reviewed the characteristics of CarbEs in relation to the metabolism of xenobiotics. Multiple isozymes of hepatic microsomal CarbE exist in various animal species [4,11]. Human CES1 and CES2 catalyze the hydrolysis of many exogenous compounds. Marsh et al. [60] studied CES1 and CES2 in multiple populations to identify SNPs and confirmed the novel SNPs in healthy European and African individuals. Sixteen SNPs were found in the CES1 gene (1 per 300 bp) and 11 in the CES2 gene (1 per 630 bp) in at least one population. Allele frequencies and estimated halotype frequencies varied significantly between African and European polulations. The catalytic efficiencies of human CarbEs 1 (hCE1) and 2 (hCE2) for several pharmaceuticals were also reported. For drugs of abuse, heroin shows the highest rates of catalysis by both enzymes. Human hCE-1, but not hCE-2, hydrolyzed the methyl ester of cocaine and the esters of meperidine and delapril. In contrast to the specificity of hCE-1 for the methyl ester of cocaine, only hCE2 hydrolyzed the benzoyl ester of cocaine (Table 2). The benzoyl group of cocaine is also hydrolyzed by serum butyrylcholinesterase [61–63]. For the remaining substrates that could be hydrolyzed by both enzymes, hCE-2 exhibited higher catalytic efficiency than hCE-1

Fig. 6. Role of carboxylesterase isozyme in drug metabolism. CES: carboxylesterase; CYP: cytochrom P450; UGT: UDP glucuronosyltransferase; MDR: multidrug resistance; MRP2: multidrug resistanceassociated protein 2.

for heroin; enzymatic conversion of 6-acetylmorphine to morphine was not known before the isolation and characterization of hCE-2 [55,64]. Takai et al. [55] also reported that hCE-2 (a form with pI 4.5) had higher activity with irinotecan (CPT-11) than hCE-1 (form with pI 5.3 CarbEs show such a broad range of substrate specificity that they can be involved in detoxification or biotransformation of many kinds of drugs as well as endogenous fatty acid esters. It has been suggested that CarbEs can be classified into four major groups according to the homology of the amino acid sequence [2,11], and the majority of CarbEs that have been identified belong to the CES1 or CES2 family. It has also been shown that striking species differences exist [4,15,64–69]. For example, Inoue et al. [67] showed that esterase activity in the dog intestine is very weak and produced no appreciable active band in a disc electrophoresis coupled with staining of esterase activity. On the other hand, esterase activities were observed in the intestines of other species (human, rat, mouse, guinea pig and rabbit) and found to produce a few active bands in an electrophoretic assay. Since pharmacokinetic and pharmacological data of ester-prodrugs obtained from preclinical experiments using various animals are generally used as references for human studies, it is important to clarify the biochemical properties of each CarbE isozyme such as substrate specificity, tissue distribution and transcriptional regulation. Geshi et al. [70] reported a single nucleotide polymorphism (SNP) in the carboxyylesterase gene that is associated with the responsiveness to imidapril medication to promotor activity. Recently, Fleming et al. [71] analyzed the crystal strucutures of hCE1 in complexes with the cholesterol-lowering drug, mevastatin.

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Table 2 Structure–activity relationship of substrates with CES1 and CES2 families Substrate

Alcohol substituent

Acyl substituent

Substrate specificity

Cocaine (methylester)

CH3 OH

CES1

Meperidine

CH3 CH2 OH

CES1

Temocapril

C2 H5 OH

CES1

CPT-11

Heroin

CH3 COOH

Methylprednisolone 21-Hemisuccinate

HOOC–CH2 –CH2 –COONa

It is well recognized that some isozymes of lipase have an esterase activity. In rodents, triglyceriol hydrolase (TGH) is highly expressed in liver as well as heart, kidney, small intestine and adipose tissues, while in humans TGH is mainly expressed in the liver, adipose tissue and small intestine. TGH localizes to the endoplasmic reticulum and lipid droplets. The TGH genes are located within a cluster of the CarbE gene on human and mouse chromosomes 16 and 8, respectively [72]. Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1 [73]. 5.2. Pharmacokinetics It is thought that CarbEs are one of the major determinants for pharmacokinetics and pharmacodynamics of ester-drugs or ester prodrugs (Fig. 6). Actually, it has been shown that dog CES1 isozyme was involved in a pulmonary first-pass effect in the disposition of a propranolol ester prodrug [74]. It has also been shown that the expression level of human CarbE isozyme was correlated with the conversion ratio of CPT-11 to SN-38, the active metabolite, which is thought to be a key step

for the chemotherapeutic action of this anti-tumor drug [57,63,65,54]. The CarbEs and the UDP-glucuronosyltransferase (UGT) families, the catalytic domains of which are localized in the luminal sides of the endoplasmic reticulum (ER) membrane, are two major enzyme groups responsible for phases I and II reactions (Fig. 7). The hydrolyzed products by CarbEs are also substrate for UGT, such as SN-38 from CPT-11. Thus, we thought CarbE-UGT interaction in the luminal sides of ER membrane is important for drug metabolism. Furthermore, hydrolyzed products of CarbEs consist of two kinds of chemical properties. One is the alcohol or phenol that are substrates for UGT, and the other is organic anions which are substrates for organic anion transporters such as multidrug resistance-associated protein 2 (MRP2) (Fig. 7). In this regard, we thought CESs are one of the major drugmetabolizing enzymes for enzyme–enzyme interaction and enzyme–transporter interaction. In terms of clinical aspects, Lentz et al. [76] reported that carboxylesterase 2, CYP 3A4, UGT1A1 and topoisomerase-1, which are all involved in activation of irinotecan, exhibit variable interindividual activity.

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6. Enzyme induction of CarbE Much interest has been shown by both clinicians and reserchers in the induction of expression of drugmetabolizing enzymes by chemicals, including medical agents, since it is one of the main reasons for drug-drug interaction causing adverse effects and for the reduction in pharmacological potencies of drugs. As for CarbEs, it has been shown that rodent CarbE isozyme(s) was induced by phenobarbital [21], aminopyrine [32], peroxisome proliferators (clofibrate, di(2ethylhexyl)phthalate, and perfluorinated fatty acids) [15–17,77]. The mouse is one of the most widely used experimental animals in the process of development of a drug, and several mouse CarbE isozymes have been identified [4,11,16,37,54,78–80]. However, information on the involvement of mouse CarbEs in drug metabolism is limited. We have reported that exposure of C57BL/6 mice to di(2-ethylhexyl) phthalate (DEHP), a peroxisome proliferator, in their diet resulted in a significant increase in the amount of CarbE protein concomitant with an increase in the level of hydrolytic activity toward xenobiotics in mouse liver microsomes [15]. Recently, we have also shown that one of the mouse CarbE isozymes induced by DEHP is mCES2/ microsomal acylcarnitine hydrolase, a CES2 family

isozyme [17]. The immunochemical study in our laboratory also suggested that mouse CES1 isozymes were induced by DEHP treatment, and this was identified as mCES1. Purification, cDNA cloning and baculovirusmediated expression of mCES1 revealed that mCES1 plays an important role in temocapril metabolism and that it belongs to the CES1A subfamily, and it was very similar to hCE-1. Therefore, mCES1 is thought to be one of the critical determinants for pharmacokinetics and pharmacodynamic actions of ester prodrugs as well as ester drugs. This work provides useful information for study of metabolism and dispositions of ester-prodrugs as well as ester-drugs. Zhu et al. [69] reported that dexamethasone caused a slight increase in human CES isozymes. Among the inducers, dexamethasone possesses a potent and interesting ability to affect CarbE expression in the rat liver. Hattori et al. [81] reported that methylprednisolone hemisuccinate (MPHS) was hydrolyzed to methylprednisolone byCarbE in rat liver microsomes and that several clinically used glucocorticoids, including dexamethasone, caused a remarkable increase in the level of this hydrolytic activity. In contrast to the report of induction of CarbE activity, some researchers have shown that the level of microsomal p-nitrophenylacetate hydrolase activity was significantly decreased by dexamethazone in rat liver microsomes in vitro. The apparent contradic-

Fig. 7. Carboxylesterase–UGT interaction in the luminal sides of ER membrane and CES–transporter interaction in the cell.

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tion in the same animal is probably due to the different methods for determination of CarbE activity by different CarbE substrates. Therefore, it is hypothesized that the CarbE isozyme contributing to p-nitrophenylacetate hydrolysis in rat liver microsomes is different from the one contributing to MPHS hydrolysis. It has been reported that dexamethasone decreased the levels of expression of rat CES1 isozymes (CES RH1, also known as ES-10 or hydrolase A, and CES RL1, also known as ES-4 or hydrolase B) in the rat liver and that the decrease in the expression levels of those enzymes was linked to the reduction in the level of pnitrophenylacetate hydrolase activity [80]. On the other hand, rat CarbE isozymes responsible for MPHS hydrolysis in rat liver microsomes have been identified to be a dexamethasone-induced CarbE isozyme that can hydrolyze MPHS in the rat liver and plasma as a member of the CES2 family, rCES2 [75]. The different biochemical properties of rCES2 from those of known rat CES1 isozymes, including its unique existence in plasma, will be useful information for studies aimed at elucidation of functions of CarbEs in drug metabolism. In addition, we also identified the gene encoding rCES2 by cDNA cloning and functional expression in Sf9 cells. Since we demonstrated that the level of the corresponding mRNA expression was markedly increased, the identification of the coding gene is valuable for studies aimed at elucidation of the molecular mechanisms by which dexamethasone induces rCES2 expression [80]. Yang et al. [82] reported that all liver carboxylesterases showed a similar pattern of change on activity, protein and mRNA levels, suggesting that TCDD coregulates the expression of these genes. TCDD is known to upregulate the expression of CYP1A1 gene through the aryl hydrocarbon receptor (AhR). The differential effects on the expression of liver carboxylesterases and CYP1A1 suggest that TCDD regulates the expression of hydrolytic enzymes via a mechanism(s) other than the AhR-mediated transcription activation, as observed in the CYP1A1 regulation. The carboxyl ester lipase (CEL) gene is highly expressed in exocrine pancreas and expression of the human CEL gene is mediated by a strong tissue-specific enhancer, which is absolutely necessary for high-level expression [83]. 7. A novel biomarker of organophosphate insecticide exposure Egasyn, an isozyme of CarbE, is an accessary protein of ␤-glucuronidase in the liver microsomes [4,36,84].

207

Egasyn-␤-glucuronidase complexes are located at the luminal sites of liver microsomal endoplasmic reticulum membrane [85]. When the organophosphorus insecticides (OP) are incorporated into the liver microsomes, the OP is tightly bound to egasyn, and subsequently, ␤-glucuronidase is dissociated and released into the blood. Consequently, the increase of plasma BG activity is good biomarker of OP exposure [86–88]. Thus, single administration of EPN, Acephate and Chlorpyrifos increased plasma BG activity to approximately over 100-fold the control level in rats [82]. Unlike OP and carbamate compounds, pyrethroid exposure is not sensitive to this biomarker because pyrethroid compounds are readily hydrolyzed by human and other mammalian carboxylesterases [89]. In conclusion, the increase in plasma BG activity after OP exposure is a much more sensitive biomarker of OP exposure than AChE inhibition in rats. 8. Conclusion Multiple CarbEs play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs. These enzymes are a major determinant of the pharmacokinetic behavior of most therapeutic agents containing an ester or amide bond. There are several factors that influence CarbE activity, either directly or at the level of enzyme regulation. In the clinical field, drug elimination is decreased and the incidence of drug–drug interactions increases when two or more drugs compete for hydrolysis by the same CarbE isozyme. Exposure to environmental pollutants or to lipophilic drugs can result in induction of CarbE activity. As several drug-metabolizing enzymes such as UGT, cytochrome P450, CarbEs have been extensively studied to clarify their substrate specificity using molecular cloning. Consequently, the novel findings obtained reveal that the substrate specificity of CarbE is, at least in part, explained by the differences in the nucleotide sequences of the individual CarbE isozymes. In addition, it becomes clear that membrane-boundtype CarbE isozymes in microsomes are required to possess the KDEL-tetrapeptide motif at the carboxy terminal of the molecule. Mammalian CarbEs have short acylglycerols, acyl-CoA and acyl-carnitine hydrolyzing activities. However, physiological roles of CarbEs still remain unclear. We should also be able to utilize in vitro experimental result to predict in vivo results. The substrate specificity of CarbE toward new prodrugs under consideration may be examined using purified CarbEs mammalian cell

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expression system, specific inhibitor and immunochemical inhibition study. However, such in vitro experiments may not make it possible to predict in vivo results, except in a particular case. We will be able to obtain enough information to compare physiologically based pharmacokinetic parameters and kinetic parameters in pro-drugs among mammalian species. In addition, we should clarify the cause of inter-individual variation in human CarbE, because CarbEs are involved in an important role for the metabolic activation of pro-drugs as a key enzyme. We have already estimated that the expression levels of CarbE isozymes are extremely different in each liver. Thus, further research on the mechanism of regulation in CarbE may serve to clarify the cause of individual variation. Finally, as the novel biomarker of organophosphorus insecticide exposure, increase of liver microsomal ␤glucuronidase is also described. The increase of plasma BG level after OP exposure is a much more sensitive and rapid biomarker than cholinesterase inhibition. We are trying to prepare a simple and rapid laboratory kit system to test OP exposure screening. Acknowledgements The authors wish to acknowledge Professor Palmer Taylor, Univresity of California at San Diego, La Jolla, and Professor William Bosron, Indiana University, Indianapolis, Indiana for providing us with valuable suggestions. We also acknowledge the colleagues at the HAB Research laboratories for preparation of this manuscript. References [1] M. Cygler, J.D. Schrag, J.L. Sussman, M. Harel, L. Silman, M.K. Gentry, B.P. Doctor, Relationship between sequence conservation and three-dimensional structure in a large family of esterases, lipases, and related proteins, Protein Sci. 2 (1993) 366–382. [2] T. Satoh, P. Taylor, W.F. Bosron, S.P. Sanghani, M. Hosokawa, B.N. La Du, Current progress on esterases: from molecular structure to function, Drug Metab. Dispos. 30 (2002) 488–493. [3] M. Hosokawa, T. Maki, T. Satoh, Multiplicity and regulation of hepatic microsomal carboxylesterases in rats, Mol. Pharmacol. 31 (1987) 579–584. [4] M. Hosokawa, T. Maki, T. Satoh, Characterization of molecular species of liver microsomal carboxylesterases of several animal species and humans, Arch. Biochem. Biophys. 277 (1990) 219–227. [5] M. Hosokawa, Y. Endo, M. Fujisawa, S. Hara, N. Iwata, Y. Sato, T. Satoh, Interindividual variation in carboxylesterase levels in human liver microsomes, Drug Metab. Dispos. 23 (1995) 1022–1027.

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